The negative predictive value of 5-day drug provocation test in nonimmediate beta-lactam allergy in children

Journal Pre-proof The Negative Predictive Value of 5-Day Drug Provocation Test in Nonimmediate Beta-Lactam Allergy in Children Ilknur Kulhas Celik, Hakan Guvenir, Selen Hurmuzlu, Muge Toyran, Ersoy Civelek, Can Naci Kocabas, Emine Dibek Misirlioglu PII:

S1081-1206(20)30004-1

DOI:

https://doi.org/10.1016/j.anai.2019.12.029

Reference:

ANAI 3121

To appear in:

Annals of Allergy, Asthma and Immunology

Received Date: 24 August 2019 Revised Date:

27 December 2019

Accepted Date: 31 December 2019

Please cite this article as: Celik IK, Guvenir H, Hurmuzlu S, Toyran M, Civelek E, Kocabas CN, Misirlioglu ED, The Negative Predictive Value of 5-Day Drug Provocation Test in Nonimmediate Beta-Lactam Allergy in Children, Annals of Allergy, Asthma and Immunology (2020), doi: https:// doi.org/10.1016/j.anai.2019.12.029. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Full title: The Negative Predictive Value of 5-Day Drug Provocation Test in Nonimmediate Beta-Lactam Allergy in Children

Running title; Five-Day Drug Provocation Test in Nonimmediate Beta-Lactam Allergy Ilknur Kulhas Celik1, Hakan Guvenir1, Selen Hurmuzlu2, Muge Toyran1, Ersoy Civelek1, Can Naci Kocabas3, Emine Dibek Misirlioglu1 1

University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology

Training and Research Hospital, Division of Pediatrics Allergy and Immunology, Ankara, Turkey 2

University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology

Training and Research Hospital, Division of Pediatrics, Ankara, Turkey 3

Division of Pediatric Allergy and Immunology, Department of Children’s Health and

Diseases, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey

Ilknur Kulhas Celik, MD: [email protected]

Hakan Guvenir, MD: [email protected]

Selen Hurmuzlu, MD: [email protected]

Muge Toyran, MD: [email protected]

Ersoy Civelek, MD: [email protected]

Can Naci Kocabas, MD: [email protected]

Emine Dibek Misirlioglu, MD: [email protected]

Correspondence: Ilknur Kulhas Celik, MD

Address: University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Division of Pediatric Allergy and Immunology, Ankara, Turkey

Phone: +90 506 3019463

Fax: +90 312 3472330

E-mail: [email protected]

Word count:2462

Table :3

Figure:1

Financial support: There are no sources of funding to declare

Conflicts of interest: None

Clinical Trial Registration: Not applicable

19-08-0420R3 Background: Extending the drug provocation test(DPT) period is recommended for patients with suspected nonimmediate beta-lactam antibiotic(BLA) allergy and negative DPT. There is no consensus regarding the duration of prolonged provocation. Objective: We aimed to determine the negative predictive value (NPV) of the 5-day extended DPT. Methods: Parents of patients with suspected non-immediate mild cutaneous reactions with BLAs who had been subjected to 5 day DPT with culprit drugs were questioned by telephone interview about re-exposure to the tested drug. Patients with reported reaction during reexposure were re-evaluated.Skin tests and serum-specific IgE analysis were not performed before first DPT. Results: A total of 355 patients had negative results in 5-day DPT. The median age at DPT was 4.2 years and 52.9% were male. The families of 255 patients(72%) could be contacted. Of these 255 patients, 179(70%) had used same drug and reactions were reported for6(3.4%) of those patients, who were subsequently re-evaluated. Five of the 6 patients had DPT with amoxicillin-clavulanate and one with cefixime. When detailed history was taken, it was found that 2 of the 5 patients with amoxicillin-clavulanate reaction had used the drug unintentionally after their reaction to re-exposure and did not have any symptoms. One of the patients underwent allergy workup and tested negative, while the other two refused the test. The patient with reported cefixime reaction underwent repeated allergy workup and tested negative. Therefore, the NPV of 5-day prolonged DPT was 98.9%. Conclusion: The 5-day prolonged DPT has high NPV and seems appropriate in duration for children with suspected nonimmediate-BLA allergy.

1

1

Introduction

2

Beta-lactam antibiotics (BLAs) are the drug classes most suspected of causing drug-related

3

hypersensitivity reactions in children1. Hypersensitivity reactions to BLAs are classified as

4

immediate or nonimmediate based on the history of the suspected reaction. Immediate

5

reactions occur within the first hour of drug administration and are mediated by the

6

production of specific IgE targeting penicillin and cephalosporin epitopes2 Immediate

7

reactions typically involve urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm,

8

gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), anaphylaxis and

9

anaphylactic shock. Nonimmediate reactions are often T cell-mediated and occur more than

10

one hour after drug administration3.

11

Nonimmediate reactions to BLAs, are usually self-limited and involve mild skin reactions3.

12

Maculopapular rashes are relatively common in the pediatric population4. In children,

13

maculopapular eruptions due to various causes, especially infectious etiologies (bacterial or

14

viral), may be misdiagnosed as beta-lactam allergy3,4. Therefore, these conditions should be

15

assessed in order to identify real hypersensitivity reactions.

16

The drug provocation test (DPT) is still the gold standard for the diagnosis of suspected

17

immediate reactions. However, the DPT protocol for nonimmediate reactions is not well

18

defined and or validated5. There are wide variations between centers in terms of dose steps,

19

time intervals between doses, and the length of prolonged DPT 6-13.

20

The duration of prolonged DPT varies from 1-10 days in previous studies

21

authors have suggested that provocation should be extended to the same duration reported

22

between beta-lactam initiation and symptom onset in the index reaction7,17. The Standards of

23

Care Committee of the British Society for Allergy and Clinical Immunology (BSACI)

24

recommends that children with mild to moderate nonimmediate reactions to beta-lactams

25

should take the therapeutic dose for 5 days at home after the initial oral challenge8.

12, 14-16

. Some

2

26

In the present study, we evaluated patients with history of negative 5-day DPT for subsequent

27

drug reactions after re-exposure to the suspected drug in order to determine the negative

28

predictive value of the 5-day extended DPT.

29

30

Methods

31

Patients and Study Design:

32

The study included all patients who presented to our pediatric allergy clinic with history of

33

nonimmediate mild cutaneous reactions attributed to BLAs between January 1, 2013 and

34

December 31, 2017 and who had undergone 5-day DPT at least 6 months earlier.

35

As routine practice in our clinic, patients evaluated in our clinic for suspected nonimmediate

36

beta-lactam allergy are given the first dose of the drug incrementally in our clinic and

37

continue taking the drug at home for 5 days.

38

Patients who underwent DPT in our clinic and developed no reaction within 5 days were

39

called by phone at least 6 months later. Those who could be contacted were asked whether

40

they had used the same drug again since the DPT and if so, whether they had any reaction.

41

Patients who reported having a reaction were invited to the clinic for re-evaluation. Based on

42

the findings from this re-evaluation, the negative predictive value of the 5-day DPT was

43

calculated.

44

The study was approved by the ethics committee of our hospital.

45

Diagnostic Protocol:

46

The initial drug allergy workup started with the standardized European Network of Drug

47

Allergy (ENDA) questionnaire for drug allergy18. A detailed history included spectrum and

3

48

timing of symptoms, dose and route of administration, list of concomitant medication, history

49

and timing of previous hypersensitivity reactions, and physical examination findings. The

50

patients’ symptoms were classified according to medical records or their guardians’

51

descriptions. If they were unable to describe the cutaneous reactions, typical pictures of

52

maculopapular and urticarial eruptions were shown and they were asked whether their

53

reaction resembled the lesions in the pictures. Reactions occurring more than one hour after

54

drug ingestion were labeled as ‘nonimmediate reactions’. Patients with nonimmediate

55

reactions that manifested clinically as maculopapular eruptions and delayed-onset

56

urticarial/angioedema were included in the study. Patients who had immediate reactions and

57

patients who had a history of severe life-threatening drug reactions (Steven-Johnson’s

58

syndrome, toxic epidermal necrolysis, hypersensitivity syndrome or drug reaction with

59

eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, nephritis,

60

pneumonitis, hepatitis, and vasculitis) were not included in the study.

61

Skin tests and serum-specific IgE analysis were not performed and patients were instead

62

subjected to DPT with the culprit drug. Drug provocation tests were done at least one month

63

after the initial reaction. Antihistaminics and all drugs that could affect DPT results were

64

stopped one week before the test. Written informed consent was taken from the patients’ legal

65

guardians.

66

Drug Provocation Test:

67

In the first day of the provocation, an incremental drug provocation test (DPT) protocol was

68

administered in our clinic. The therapeutic daily dose of the drug was calculated according to

69

age and weight of the patient The ENDA guidelines for DPTs were followed carefully19. The

70

DPT involved administering the suspected drug in divided doses every 30 min until reaching

71

a cumulative dose approximately the age/weight-adjusted daily dose of the drug. The

4

72

provocation was given maximally in 5 doses in order to prevent the possibility of patient

73

desensitization19,20. The test was discontinued in the event of any reaction. Administration

74

was open and performed by a physician with full resuscitation backup. The DPT was

75

considered positive if any objective symptoms or signs (e.g., urticaria, angioedema,

76

circulatory depression, wheezing, or rhonchi) were documented. After the last dose had been

77

administered without a reaction, the patient was kept under surveillance for at least 2 hours

78

and told to continue to use the drug in two divided doses for 5 days at home to identify

79

patients with delayed reactions. The doses (mg/kg) used in DPT are shown on Table 1. The

80

extended 5-day DPT was considered negative if no reaction occurred by the end of this

81

period.

82

Re-evaluation of Patients with Reported Reactions upon Re-exposure

83

Patients with reported reactions following repeated exposure after a negative DPT were

84

invited to our clinic for re-evaluation Prick and intradermal skin testing including the

85

penicillin test kit

86

(MDM)], penicillin G (10,000 IU/mL), amoxicillin-clavulanate (20 mg/mL), and the

87

suspected drug were performed .We used Diater DAP kit (DAP kit; Madrid, Spain) as

88

penicillin test kit. All of the drugs were initially tested on the volar forearm skin by using the

89

prick method and reactions were considered positive when a wheal diameter equal or higher

90

than 3 mm of the negative control with surrounding erythema was present 20 minutes later.

91

When prick tests yielded negative results, 0.02 mL of the relevant agent was injected

92

intradermally on volar forearm skin. Readings were made at 20 minutes,48 hours and 72

93

hours after injections. Results were considered positive when an increase of 3 mm in the

94

wheal diameter accompanied by erythema was present. Positive controls for prick tests were

95

carried out with histamine at 10 mg/mL. A negative control sample, of 0.9% NaCl, for prick

96

and intradermal tests was used. Drug provocation test with penicillin-V followed by the

[benzylpenicilloylpoly-L-lysine (PPL), minor determinant mixture

5

97

suspected beta-lactam were performed for patients with negative skin tests . The extended 5-

98

day DPT for suspected drug was considered negative if no reaction occurred

99

Statistical Analyses:

100

Statistical analyses were performed using the SPSS v.22 statistical software package (IBM,

101

Chicago, IL, USA) for Windows. Numbers and percentages were reported for discrete

102

variables; continuous variables were expressed as mean and standard deviation for data with

103

normal distribution and as median and interquartile range (IQR) for data not normally

104

distributed. The chi-square (χ2) test was used to compare nonparametric data; the Mann–

105

Whitney U test was used in comparisons of nonnormally distributed continuous data and

106

independent samples t test for normally distributed continuous data. P value < 0.05 was

107

considered statistically significant.

108

Results

109

During the study period, 365 patients underwent DPT in our clinic for suspected

110

nonimmediate beta-lactam BLA allergy and the results were negative in 355 (97.2%) of those

111

patients.

112

Drug provocation tests’ results were positive in 10 of the 365 patients. All of patients with

113

positive DPT developed mild cutaneous signs. Three Four patients developed a reaction after

114

the first dose, 4 patients on day 2, and 2 patients on day 4 of provocation. Drug provocation

115

tests’ results from 135 children included between January 2014 and January 2015 have been

116

previously published 15.

117

All 355 pediatric patients whose initial DPT was negative and who continued to use the

118

suspicious drug at home for 5 days were included in the study.

6

119

Of these patients, 255 (72%) were reached by phone (Figure 1). There was no statistically

120

significant difference between the patients who were and were not reachable by phone in

121

terms of their characteristics (Table 2).

122

The most common complaint of the 255 patients who were reachable by phone was

123

maculopapular rash (66.2%), and other complaints at time of admission are shown in Table 2.

124

The suspected drug was a penicillin in 210 (82.4%) of the cases and a cephalosporin in the

125

remaining 45 patients. The most commonly suspected drug from the penicillin group was

126

amoxicillin-clavulanate (76.4%). Suspected drugs reported by the patients are given in Table

127

2.

128

After conducting the phone interviews, it was determined that 179 (70%) of the 255 patients

129

had used the same drug again since the test, 6 (3.4%) of whom had developed a reaction.

130

These 6 patients were invited for re-evaluation. Characteristics of the patients re-evaluated are

131

given in Table 3.

132

Characteristics of the Re-evaluated Patients:

133

Six patients reported reaction during re-exposure. Five of these patients had had DPT with

134

amoxicillin-clavulanate and 1 patient with cefixime.

135

Upon investigation of prescription data for 2 of the 5 patients with reported reaction to

136

amoxicillin-clavulanate, it was found that they had later used the same drug again without

137

realizing and did not develop any reaction. These two patients were considered reaction

138

negative and no diagnostic tests were performed. Thus 4 of the 6 patients were re-evaluated.

139

One of the other 3 patients reported urticaria 4 hours after dose 4 on day 2 of subsequent use.

140

This patient underwent classic penicillin test and amoxicillin-clavulanate prick and

141

intradermal skin test with early and delayed reading. Results of the skin tests were negative.

7

142

Drug provocation test was then performed with penicillin-V and amoxicillin-clavulanate, and

143

the results were negative. One of the other 2 patients reported maculopapular rash 4 hours

144

after dose 6 on day 3 of repeated use, and was also subjected to standard penicillin test and

145

amoxicillin-clavulanate prick and intradermal skin test with early and delayed reading. The

146

skin tests were negative. Drug provocation test with penicillin-V was also negative. Drug

147

provocation test with amoxicillin–clavulanate was ordered but could not be performed

148

because the family did not consent to the procedure. The last patient did not undergo any

149

diagnostic tests because consent could not be obtained.

150

The patient who reported reaction with cefixime, reported urticaria 6 hours after dose 5 on

151

day 5 of repeated use, so standard penicillin test with skin prick and intradermal early and

152

delayed reading was performed. The skin tests were negative, after which DPT was done first

153

with penicillin-V and then with cefixime, both of which were negative.

154

As one of our patients did not consent for re-evaluation and one other could not be fully re-

155

evaluated (DPT with penicilin V negative but did not consent for amoxicilin), these 2 of 355

156

patients were considered reaction positive, resulting in a negative predictive value of 98.8%

157

with 5-day extended DPT for nonimmediate mild cutaneous reactions associated with beta-

158

lactam antibiotics.

159

Discussion

160

In our study evaluating pediatric patients presenting to our hospital with suspected

161

nonimmediate beta-lactam allergy, we determined that 365 patients underwent DPT and the

162

result was negative in 355 (97.2%). Of the 255 of these patients who could be reached by

163

phone, 179 (70%) used the same drug again after the test, and 4 developed reaction upon re-

164

exposure. Of the 4 patients who were re-evaluated, 2 patients underwent allergy workup and

165

tested negative, while the other two refused the test. We determined that extended DPT with

8

166

5-day provocation had a high (98.8%) negative predictive index in patients with mild

167

cutanous reactions due to suspected nonimmediate beta-lactam allergy.

168

Nonimmediate mild cutaneous reactions are the most frequent drug hypersensitivity reactions

169

to beta-lactam antibiotics 3. Suspected nonimmediate reactions have lower confirmation ratio

170

with allergy workup. In a prospective study including 1026 children with a mean age of 7.7

171

years, results of complete allergy workup confirmed nonimmediate hypersensitivity reactions

172

to beta-lactam antibiotics in only 7.4% of the children21. Mill et al. evaluated 818 pediatric

173

patients (median age: 1.7 years) with a history of amoxicillin hypersensitivity and reported

174

that the majority of the children showed nonimmediate benign reactions to amoxicillin and

175

only 48 (5.8%) had a positive DPT 22. In our study the confirmation rate after allergy workup

176

was 2.8% in our patients, whose median age was 4.4 years. The lower confirmation rate in our

177

study may be due to our young patient group, because most skin eruptions during beta-lactam

178

treatment in children are likely due to viral infections, but can mimic allergic reaction23.

179

Although DPT is the gold standard when investigating pediatric hypersensitivity reactions to

180

beta-lactams in children, there is no consensus on the optimal length of the DPT protocol to

181

investigate nonimmediate reactions to beta-lactam antibiotics. The duration of prolonged DPT

182

varies from 1-10 days in previous studies. While shorter protocols are more efficient and have

183

fewer side effects, longer protocols may increase the sensitivity of DPT 3. Although no studies

184

have compared short and long protocols, it was reported that 7-day amoxicillin treatment has

185

a significantly impact on the gut microbiota24. On the other hand, the occurence of a hapten

186

protein or hapten peptide specific immune response needs time to form the hapten protein

187

complex, process the hapten protein, present the hapten peptides on HLA molecules and

188

expand drug‐specific T and B cells. This time is approximately

189

amoxicillin25.

7‐12 days for

9

190

DPT protocols of different lengths have been used and their negative predictive values

191

determined in various studies. Mill et al. reported a negative predictive value of 89.1% in 1-

192

day DPT for suspected amoxicillin allergy22. Tonsonla Tour et al. reported a negative

193

predictive value of 96.7% in patients who underwent 3-day DPT for suspected penicillin

194

allergy26.Labrosse et al. reported this value to be 97.6% in their study evaluating the negative

195

predictive value of 5-day DPT for suspected amoxicillin allergy14. In the present study, we

196

determined a negative predictive value of 98.8% for 5-day DPT in patients presenting with a

197

history of nonimmediate beta-lactam allergy.

198

The negative predictive value of 5-day provocation for extended DPT was high in our study.

199

However, because none of our patients underwent DPT for other lengths of time, we could not

200

compare negative predictive value between different provocation durations.

201

Although recent studies have shown that the negative predictive value of 1-day DPT is

202

comparable to that of longer DPTs, there are also studies indicating that extended DPTs are

203

better in terms of future patient and physician drug compliance23. Ratzon et al. compared 26

204

patients who underwent 7-day DPT and 23 patients who underwent 1-day DPT for diagnosis

205

of beta-lactam antibiotic allergy and found that the frequency of using the same drug again

206

was higher in patients who underwent 7-day DPT 27. Moreover, in the study by Labrosse et al.

207

comparing pediatric patients with a history of amoxicillin allergy who underwent 5-day DPT

208

versus single-dose DPT, 25% of the families or physicians of patients who underwent single-

209

dose DPT were hesitant to use the same drug again, while this rate was only 1.3% for patients

210

who underwent 5-day DPT14. As mentioned earlier, we could not make such comparisons in

211

the present study because all of our patients underwent 5-day DPT.

212

In conclusion the 5-day prolonged drug provocation test had high negative predictive value in

213

our study. Therefore, we believe that 5 days is an effective duration for extended DPT in the

10

214

diagnosis of nonimmediate beta-lactam allergy. Further studies including different time period

215

are needed to better define the optimal length of DPT for nonimmediate reactions to BL

216

antibiotics.

217

1

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9. Zambonino MA, Corzo JL, Munoz C, et al. Diagnostic evaluation of hypersensitivity reactions to beta -lactam antibiotics in a large population of children. Pediatr Allergy Immunol 2014;25(1):80 -87 10. Messaad D, Sahla H, Benahmed S,et al. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction. Ann Intern Med 2004;140(12):1001 1006. 11. Caubet JC, Frossard C, Fellay B, et al. Skin tests and in vitro allergy tests have a poor diagnostic value for benign skin rashes due to beta -lactams in children. Pediatr Allergy Immunol 2015;26(1):80 -82 12. Mori F, Cianferoni A, Barni S, et al. Amoxicillin allergy in children: five-day drug provocation test in the diagnosis of nonimmediate reactions. J Allergy Clin Immunol Pract 2015; 3:375–380 13. Confino-Cohen R, Rosman Y, Meir-Shafrir K, et al. Oral challenge without skin testing safely excludes clinically significant delayed-onset penicillin hypersensitivity. J Allergy Clin immunol. In Pract.2017;5(3):669–675. 14. Labrosse R, Paradis L, Lacombe J, et al. Efficacy and safety of five-day challenge for the evaluation of non-severe amoxicillin allergy in children. J Allergy Clin immunol.In Pract. J Allergy Clin Immunol Pract. 2018 ;6(5):1673-1680. 15. Vezir E, Dibek Misirlioglu E, Civelek E, et al. Direct oral provocation tests in nonimmediate mild cutaneous reactions related to beta-lactam antibiotics. Pediatr Allergy Immunology. 2016;27(1):50–54. 16. Borch JE, Bindslev-Jensen C. Full-course drug challenge test in the diagnosis of delayed allergic reactions to penicillin. Int Arch Allergy Immunol 2011; 155:271–274.

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17. Lezmi G, Alrowaishdi F, Bados-Albiero A, et al. Nonimmediate-reading skin tests and prolonged challenges in nonimmediate hypersensitivity to betalactams in children. Pediatr Allergy Immunol Pediatr Allergy Immunol. 2018 ;29(1):84-89. 18. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy 1999: 54: 999–1003. 19. Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003: 58: 854–63. 20. Celik GE, Pichler WJ, and Adkinson NF, Jr. Drug Allergy. In. Middleton’s Allergy Principles and Practice, Eighth edition. Adkinson NF, Bochner BS, Burks AW, et al. (Eds). Saunders: Elsevier 1274 –1295, 2014 21. Atanaskovic-Markovic M, Gaeta F, Medjo B, et al. Non-immediate hypersensitivity reactions to beta-lactam antibiotics in children - our 10 years experience in allergy work-up. Pediatr Allergy Immunol 2016; 27: 533-8 22. Mill C, Primeau MN, Medoff E, et al. Assessing the diagnostic properties of a graded oral provocation challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin in children. JAMA Pediatr 2016; 170:e160033 23. Graham F, Tsabouri S, Caubet JC. Hypersensitivity reactions to beta-lactams in children. Curr Opin Allergy Clin Immunol. 2018;18(4):284-290 24. Brunser O, Gotteland M, Cruchet S, et al. Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment. Pediatr Res 2006; 59:451–456 25. Pichler WJ. Immune pathomechanism and classification of drug hypersensitivity. Allergy. 2019;74(8):1457-1471.

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26. Tonson la Tour A, Michelet M, Eigenmann PA, Caubet JC. Natural History of Benign Nonimmediate Allergy to Beta-Lactams in Children: A Prospective Study in Retreated Patients After a Positive and a Negative Provocation Test. J Allergy Clin Immunol Pract. 2018;6(4):1321-1326. 27. Ratzon R, Reshef A, Efrati O, Deutch M, Forschmidt R, Cukierman-Yaffe T, Kenett R, Kidon MI. Impact of an extended challenge on the effectiveness of β-lactam hypersensitivity investigation. Ann Allergy Asthma Immunol. 2016;116(4):329-33.

Table 1. Drug doses used in oral provocation test Drug

Dose

Amoxicillin-clavulanic acid

40 mg/kg/day

Amoxicillin

40 mg/kg/day

Ampicillin-sulbactam

50 mg/kg/day

Penicillin V

25 mg/kg/day

Cefixime

8 mg/kg/day

Cefixime-clavulanic acid

8 mg/kg/day

Cefuroxime

20 mg/kg/day

Cefdinir

14 mg/kg/day

Cefprozil

15 mg/kg/day

Cefaclor

20 mg/kg/day

Cefpodoxime

10 mg/kg/day

Table 2. Comparison of the patients contacted and those who could not be contacted

Gender n,% female male Age at reaction (years) median (IQR) Age at DPT (years) median (IQR) Interval between DPT and reaction (months) median (IQR) Duration of exposure at time of reaction (days) median (IQR) Number of doses taken at time of reaction median (IQR) Interval between last dose and reaction (hours) median (IQR) Eosinophil count median (IQR) IgE level median (IQR) Presence of allergic disease, n (%) Suspected drugs, n (%) Penicillin Amoxicillin-clavulanic acid Amoxicillin Penicillin V Ampicillin-sulbactam Cephalosporin

Patients contacted (n=255)

Patients who could not be contacted (n=100)

p

120 (47.1) 135 (52.9)

45 (45) 55 (55)

0.4

3.0 (1.5-5.98)

3.0 (1.5-5.82)

0.83

4.2 (1.98-7.02)

4.17 (2.05-6.89)

0.85

3.12 (2.04-7.74)

3.12 (2.04-8.84)

0.91

2 (2-5)

2 (2-5)

0.6

4 (3-9)

4 (3-9.7)

0.62

8 (5-10)

8 (5-10)

0.63

1.9 (0.8-3)

1.5 (0.8-3.3)

0.41

20 (12-85) 36 (14.1)

27 (14-83) 11 (11)

0.34 0.47

210 (82.4) 195 6 6 3 45 (17.6)

86 (86) 78 3 3 2 14 (14)

0.76

0.85

Cefixime Cefuroxime Cefdinir Cefprozil Cefpodoxime Cefixime + clavulanic acid Presenting reaction, n (%) Maculopapular rash Urticaria Urticaria + Angioedema Hyperemia Angioedema Hyperemia + Angioedema Maculopapular rash + Angioedema

15 14 9 4 2 1

5 4 3 2 -

170 (66.2) 47 (18.0) 14 (6.1) 14 (6.1) 7 (1.9) 2 (0.6) 1 (0.3)

70 (70) 15 (15) 7 (7) 7 (7) 1 (1) -

Table 3. Result of re-evaluation Drug

Presenting reaction

First reaction time 2nd day 10 h after last dose

Subsequent use reaction Urticaria

Second reaction time 2nd day 5 h after last dose

Patient 1

Amoxicillinclavulanate

Urticaria + Angioedema

Patient 2

Amoxicillinclavulanate

Patient 3

Result of re-evulation

Maculopapular rash

2nd day 22 h after last dose

Maculopapular rash

2nd day 3 h after last dose

Used the drug unintentionally after their reaction to re-exposure and did not have any symptoms

Amoxicillinclavulanate

Maculopapular rash

2nd day 4 h after last dose

Urticaria

2nd day 4 h after last dose

Tests were negative.

Patient 4

Amoxicillinclavulanate

Urticaria

1st day 2 hour after last dose

Maculopapular rash

3rd day 4 h after last dose

Refused re-evaluation

Patient 5

Amoxicillinclavulanate

Urticaria + Angioedema

6th day 6 h after last dose

Urticaria

2nd day 4 h after last dose

Refused re-evaluation

Patient 6

Cefixime

Maculopapular rash

2nd day 10 h after last dose

Urticaria

5th day 6 h after last dose

Tests were negative

Used the drug unintentionally after their reaction to re-exposure and did not have any symptoms

Figure1.Algorithm of the study

Patients underwent DPT (n=355)

Patients who were contacted (n=255)

Patients hadn’t developed a reaction after subsequent use

Patients had developed a reaction after subsequent use (n=4)

(n=175)

Re-evaluation

Refused re-evaluation (n=2)

Negative (n= 2)

Patients had not received the drug again (n=76)